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A more recent version of this article appeared on August 1, 2007

Published online before print April 24, 2007
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0606396

Received for publication June 13, 2006.
Revised January 29, 2007.
Accepted for publication January 29, 2007.

Article

Maturation of the mucosal immune system underlies colitis susceptibility in interleukin-10-deficient (IL-10-/-) mice

Michele R. Etling *, Sarah Davies {dagger}, Melanie Campbell {dagger}, Raymond W. Redline *, Pingfu Fu {ddagger}, and Alan D. Levine *{dagger}{ddagger}{sect}@

Departments of *Pathology, {dagger}Medicine, and {sect}Pharmacology and the {ddagger}Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

@ To whom correspondence should be addressed. E-mail: alan.levine{at}case.edu.


  Abstract

Elevated mucosal IL-12/23p40 and IFN-{gamma} accompany early inflammation in IL-10- deficient (IL-10-/-) mice and then later decline while inflammation persists. This report addresses whether this cytokine profile reflects disease progression or inherent, age-related changes in mucosal immunity. IL-10-/- and wild-type (WT) mice were maintained in an ultrabarrier facility or transferred to conventional housing at 3, 12, or 30 weeks of age. Weight, stool changes, and histologic features were followed. Lamina propria mononuclear cells were cultured for cytokine analysis by ELISA. Ultrabarrier-housed IL-10-/- mice are statistically indistinguishable from WT mice by weight, disease activity index, and histologic inflammation. IL-10-/- mice but not WT, transferred at 3 weeks, develop colitis gradually, reaching a significant, sustained maximum by 15 weeks of age. Transfer at 12 weeks induces rapid disease onset in both strains, maximal at 15 weeks of age. Inflammation persists in IL-10-/-, and WT recover. IL-10-/- and WT mice transferred at 30 weeks demonstrate transient diarrhea and weight loss but no chronic inflammation. Probiotics delay symptom onset only in the 12-week-old group. IFN-{gamma} production from ultrabarrier-housed IL-10-/- mice is elevated at 12 weeks of age, and older animals have decreased IFN-{gamma} and increased IL-4. IL-10 is important for suppressing inflammation after transfer at 3 weeks of age and limiting inflammation after transfer at 12 weeks but has little influence at 30 weeks of age. Colitis onset, progression, and response to probiotic therapy vary with immune system age, suggesting that a distinct, Th1-driven, age-dependent cytokine profile may contribute to increased colitis susceptibility in otherwise healthy mice.

Key Words: aging • cytokine • cytokine array






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